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RationaleAlcohol has both acute and chronic effects on neuroimmune signaling, including triggering pro-inflammatory cytokine release by microglia. Minocycline, a second-generation tetracycline antibiotic, inhibits microglial activation and reduces neuroinflammation in preclinical studies. In mice, minocycline also reduces ethanol intake, attenuates ethanol-induced conditioned place preference, and inhibits ethanol-induced microglial activation and pro-inflammatory cytokine release.ObjectiveHere, for the first time, we tested the effects of minocycline on subjective response to ethanol and acute ethanol-induced inflammation in humans.MethodsForty-eight heavy drinkers participated in a double-blind, placebo-controlled trial in which they were randomized to receive placebo, 100 mg, or 200 mg of minocycline for 10 days. Each subject then underwent two experimental sessions in which they were given a fixed dose of intravenous ethanol using a “clamp” procedure (100 mg%) or placebo (normal saline) on days 8 and 10 of treatment. ResultsMinocycline was well tolerated, but there was no effect of either dose of minocycline on subjective response to ethanol or ethanol-induced craving; minocycline effects on cognitive function seem to interact with age. Minocycline treatment did not alter serum cytokine levels at baseline or during ethanol-exposure, although certain baseline cytokine levels predict sedative response to ethanol. ConclusionThese findings indicate that a short-term treatment with minocycline may not alter ethanol-related inflammation or subjective response to ethanol in humans. Further research is needed to identify pharmacological agents with robust effects on ethanol-induced inflammation to determine whether neuroimmune modulation represents a viable treatment strategy for alcohol use disorder.

Rationale Alcohol effects on behavioral and cognitive mechanisms influence impaired driving performance and decisions to drive after drinking (Barry 1973 ; Moskowitz and Robinson 1987 ). To date, research has focused on the ascending limb of the blood alcohol curve, and there is little understanding of how acute tolerance to impairment of these mechanisms might influence driving behavior on the descending limb. Objectives To provide an integrated examination of the degree to which alcohol impairment of motor coordination and inhibitory control contributes to driving impairment and decisions to drive on the ascending and descending limbs of the blood alcohol curve. Methods Social-drinking adults ( N  = 20) performed a testing battery that measured simulated driving performance and willingness to drive, as well as mechanisms related to driving: motor coordination (grooved pegboard), inhibitory control (cued go/no-go task), and subjective intoxication. Performance was tested in response to placebo and a moderate dose of alcohol (0.65 g/kg) twice at comparable blood alcohol concentrations: once on the ascending limb and again on the descending limb. Results Impaired motor coordination and subjective intoxication showed acute tolerance, whereas driving performance and inhibitory control showed no recovery from impairment. Greater motor impairment was associated with poorer driving performance under alcohol, and poorer inhibitory control was associated with more willingness to drive. Conclusions Findings suggest that acute tolerance to impairment of motor coordination is insufficient to promote recovery of driving performance and that the persistence of alcohol-induced disinhibition might contribute to risky decisions to drive on the descending limb.

We assessed multiple examinations and assessment tools to develop a standardized measurement of alcohol intoxication to aid medical decision making in the Emergency Department. Volunteers underwent an alcohol challenge. Pre- and post-alcohol challenge, subjects were videotaped performing three standardized clinical examinations: (1) Standardized Field Sobriety Test (SFST) examination, (2) Hack's Impairment Index (HII) examination, and (3) Cincinnati Intoxication Examination (CIE). Emergency clinicians evaluated the level of intoxication using five standardized assessment tools in a blinded and randomized fashion: (1) SFST assessment tool (range 0–18), (2) HII assessment tool (range 0–1), (3) St. Elizabeth Alcohol Intoxication Scale (STE, range 0–17), (4) a Visual Analog Scale (VAS, range 0–100), and (5) a Binary Intoxication Question (BIQ). Construct validity was assessed along with inter- and intra-rater reliability. Median scores pre- and post-alcohol challenge were: SFST 6 (interquartile range 5) and 11 (3), respectively; HII 0 (0.05), 0.1 (0.1); STE 0 (1), 1 (2); VAS 10 (22), 33 (31). For BIQ, 59% and 91% indicated intoxication, respectively. Inter-rater reliability scores were: SFST 0.71 (95% confidence interval 0.48–0.86) to 0.93 (0.88–0.97) depending on examination component; HII 0.90 (0.82–0.95); STE 0.86 (0.75–0.93); VAS 0.92 (0.88–0.94); BIQ 0.3. Intra-rater reliability scores were: SFST 0.74 (0.64–0.82) to 0.87 (0.81–0.91); HII 0.85 (0.79–0.90); STE 0.78 (0.68–0.85); VAS 0.82 (0.74–0.87); BIQ 0.71. VAS reliability was best when paired with the HII and SFST examinations. HII examination, paired with either a VAS or HII assessment tool, yielded valid and reliable measurements of alcohol intoxication.

Rationale Exposure to alcohol-related cues leads to increased alcohol consumption, and this may be partially attributable to momentarily impaired impulse control. Objectives We investigated if exposure to alcohol cues would impair inhibitory control and if the extent of this impairment would partially mediate the effect of alcohol cues on subsequent voluntary alcohol consumption. Methods We recruited 81 heavy drinkers (50 female) who completed baseline measures of inhibitory control (stop-signal task) and subjective craving before random allocation to an alcohol cue exposure or control group. The alcohol cue exposure group then completed a second stop-signal task (with embedded alcohol cues) with concurrent exposure to olfactory alcohol cues, in an alcohol context. The control group completed a second stop-signal task (with embedded water cues), accompanied by exposure to water cues, in a neutral context. Then, subjective craving and ad libitum alcohol consumption were measured in all participants. Results Inhibitory control worsened (compared to baseline) to a greater extent in the alcohol cue exposure group compared to the control group. Craving and ad libitum alcohol consumption were elevated in the alcohol cue exposure group compared to the control group, although the group difference in alcohol consumption fell short of statistical significance. In support of our hypotheses, multiple mediation analyses demonstrated that elevated ad libitum alcohol consumption following alcohol cue exposure was partially mediated by both impaired inhibitory control and increased craving. Conclusions These findings suggest that state fluctuations in inhibitory control are a potential mechanism through which alcohol cues increase drinking behaviour.

There is preliminary evidence that approach avoid training can shift implicit alcohol associations and improve treatment outcomes. We sought to replicate and extend those findings in US undergraduate social drinkers (Study 1) and at-risk drinkers (Study 2). Three adaptations of the approach avoid task (AAT) were tested. The first adaptation - the approach avoid training - was a replication and targeted implicit alcohol approach associations. The remaining two adaptations - the general identity and personalized identity trainings - targeted implicit drinking identity associations, which are robust predictors of hazardous drinking in US undergraduates. Study 1 included 300 undergraduate social drinkers. They were randomly assigned to real or sham training conditions for one of the three training adaptations, and completed two training sessions, spaced one week apart. Study 2 included 288 undergraduates at risk for alcohol use disorders. The same training procedures were used, but the two training sessions occurred within a single week. Results were not as expected. Across both studies, the approach avoid training yielded no evidence of training effects on implicit alcohol associations or alcohol outcomes. The general identity training also yielded no evidence of training effects on implicit alcohol associations or alcohol outcomes with one exception; individuals who completed real training demonstrated no changes in drinking refusal self-efficacy whereas individuals who completed sham training had reductions in self-efficacy. Finally, across both studies, the personalized identity training yielded no evidence of training effects on implicit alcohol associations or alcohol outcomes. Despite having relatively large samples and using a well-validated training task, study results indicated all three training adaptations were ineffective at this dose in US undergraduates. These findings are important because training studies are costly and labor-intensive. Future research may benefit from focusing on more severe populations, pairing training with other interventions, increasing training dose, and increasing gamification of training tasks.

Previous studies have demonstrated that alcohol consumption impairs neuroplasticity in the motor cortex. However, it is unknown whether alcohol produces a similar impairment of neuroplasticity in the dorsolateral prefrontal cortex (DLPFC), a brain region that plays an important role in cognitive functioning. The aim of the current study was to evaluate the effect of alcohol intoxication on neuroplasticity in the DLPFC. Paired associative stimulation (PAS) combined with electroencephalography (EEG) was used for the induction and measurement of associative LTP-like neuroplasticity in the DLPFC. Fifteen healthy subjects were administered PAS to the DLPFC following consumption of an alcohol (1.5 g/l of body water) or placebo beverage in a within-subject cross-over design. PAS induced neuroplasticity was indexed up to 60 minutes following PAS. Additionally, the effect of alcohol on PAS-induced potentiation of theta-gamma coupling (an index associated with learning and memory) was examined prior to and following PAS. Alcohol consumption resulted in a significant impairment of mean (t = 2.456, df = 13, p = 0.029) and maximum potentiation (t = −2.945, df = 13, p = 0.011) compared to the placebo beverage in the DLPFC and globally. Alcohol also suppressed the potentiation of theta-gamma coupling by PAS. Findings from the present study provide a potential neurophysiological mechanism for impairment of cognitive functioning by alcohol.

The Concealed Information Test (CIT) enables the detection of certain (e.g., crime-relevant or personal) information, even if participants aim to conceal their knowledge. The current preregistered study investigated whether previously observed impairing effects of alcohol intoxication on participants’ performance in a reaction time CIT (RT CIT) field study also translate to a laboratory environment. In contrast to the previous study of Suchotzki and Gamer (Sci Rep 8:7825, 2018) in which alcohol consumption was voluntary and self-administered, the current study used a randomized assignment of participants to either an alcohol group ( n  = 88; receiving a drink with 3 cl alcohol) or a sober control group ( n  = 89; receiving a drink with just some alcohol drops to hide group assignment). After drink administration, participants completed an RT CIT, in which they were instructed to hide knowledge of their own identity. Blood alcohol concentration (BAC) was estimated via breath alcohol ratio. In contrast to the previous field study, results revealed no differences in CIT-performance between intoxicated and sober participants. Aside from questioning the robustness of the result of the previous field study, our results also point to a number of interesting theoretical explanations for the discrepancy between both results, which are elaborated in the discussion.

While the deleterious effects of acute ethyl alcohol intoxication on executive control are well-established, the underlying spatiotemporal brain mechanisms remain largely unresolved. In addition, since the effects of alcohol are noticeable to participants, isolating the effects of the substance from those related to expectations represents a major challenge. We addressed these issues using a double-blind, randomized, parallel, placebo-controlled experimental design comparing the behavioral and electrical neuroimaging acute effects of 0.6 vs 0.02 ​g/kg alcohol intake recorded in 65 healthy adults during an inhibitory control Go/NoGo task. Topographic ERP analyses of covariance with self-reported dose expectations allowed to dissociate their neurophysiological effects from those of the substance. While alcohol intoxication increased response time variability and post-error slowing, bayesian analyses indicated that it did not modify commission error rates. Functionally, alcohol induced topographic ERP modulations over the periods of the stimulus-locked N2 and P3 components, arising from pre-supplementary motor and anterior cingulate areas. In contrast, alcohol decreased the strength of the response-locked anterior cingulate error-related component but not its topography. This pattern indicates that alcohol had a locally specific influence within the executive control network, but disrupted performance monitoring processes via global strength-based mechanisms. We further revealed that alcohol-related expectations induced temporally specific functional modulations of the early N2 stimulus-locked medio-lateral prefrontal activity, a processing phase preceding those influenced by the actual alcohol intake. Our collective findings thus not only reveal the mechanisms underlying alcohol-induced impairments in impulse control and error processing, but also dissociate substance- from expectations- related functional effects. •ERPs were recorded during a Go/NoGo task after 0.6 ​g/kg acute alcohol intoxication.•Alcohol induced topographic ERP modulations of the preSMA/ACC N2 and P3 components.•Alcohol induced global field power ERP modulations of the ACC ERN component.•Alcohol-related expectations modulated early mediolateral PFC N2 component.•Spatiotemporal dissociation of the effect of alcohol from those of the related expectations.

Organisms have sophisticated subcellular compartments containing enzymes that function in tandem. These confined compartments ensure effective chemical transformation and transport of molecules, and the elimination of toxic metabolic wastes 1 , 2 . Creating functional enzyme complexes that are confined in a similar way remains challenging. Here we show that two or more enzymes with complementary functions can be assembled and encapsulated within a thin polymer shell to form enzyme nanocomplexes. These nanocomplexes exhibit improved catalytic efficiency and enhanced stability when compared with free enzymes. Furthermore, the co-localized enzymes display complementary functions, whereby toxic intermediates generated by one enzyme can be promptly eliminated by another enzyme. We show that nanocomplexes containing alcohol oxidase and catalase could reduce blood alcohol levels in intoxicated mice, offering an alternative antidote and prophylactic for alcohol intoxication. Two or more enzymes encapsulated in a thin polymer shell can lower blood alcohol levels in intoxicated mice, offering a way to prevent liver injury arising from the overconsumption of alcohol.

Rationale While alcohol intoxication is known to increase disinhibited behavior, the degree to which disinhibition occurs appears to depend on a number of factors including executive functioning ability. However, the neural mechanisms by which individual differences in executive functioning lead to variable degrees of disinhibition remain unclear. Objectives The aim of the current study was to examine the neural mechanisms by which individual differences in working memory (WM) capacity moderate alcohol-induced disinhibition. Methods Seventeen heavy-drinking males participated in a within-subjects design in which two sessions were completed: an alcohol session (.82 g/kg) and a control session. Participants completed a go/no-go task while undergoing functional magnetic resonance imaging (fMRI) after ingestion of the control or alcohol beverage. WM capacity was measured using an operation span task. Results Significant interactions of session and WM capacity emerged in contrasts examining successful response inhibition within superior temporal gyrus and unsuccessful inhibition in regions within the default mode network. In all cases, individuals with low WM capacity demonstrated a relative decrease in blood oxygen level-dependent (BOLD) response during the alcohol compared to control session, whereas the high-WM-capacity group demonstrated relative increases in BOLD response in the alcohol compared to control session. Conclusions Low WM capacity appears to be associated with decreased neural response to signals indicating a need for behavioral control, an effect that may lead to increased difficulty with inhibiting responses and increased negative consequences from alcohol intoxication.